Real-World Impact of PARP Inhibitors on Progression-Free Survival In Ovarian Cancers: A Causal Heterogeneity Analysis Based on Organ Vulnerability
Abstract
Purpose
PARP inhibitors are standard maintenance therapy for ovarian cancer, yet how baseline organ function modifies their comparative effectiveness beyond molecular biomarkers remains unclear. Using real-world data, we estimate the causal effect of molecular markers and assess whether organ vulnerability modifies progression-free survival differences between olaparib and niraparib.
Methods
We analyzed a retrospective cohort of 604 ovarian cancer patients treated with olaparib or niraparib at Hunan Cancer Hospital. A 0-3 organ vulnerability score (OVS), derived from routine pre-treatment labs reflecting bone marrow, hepatic/renal, and systemic reserve, was used to stratify patients. In 280 patients with BRCA status, causal inference methods estimated the average treatment effect of BRCA on PFS. In the full cohort, G-computation with Cox models assessed the conditional effect of drug type across OVS levels.
Results
BRCA mutations were significantly associated with longer PFS (HR = 0.664, 95% CI: 0.522-0.844; P = 0.001), with consistent results across sensitivity analyses. Organ vulnerability significantly modified the comparative effectiveness of PARP inhibitors (interaction HR = 2.131, 95% CI: 1.218-3.727; P = 0.008). Among low-vulnerability patients (OVS 0-1, n = 507), olaparib showed a modest PFS benefit over niraparib (HR = 0.786, P = 0.039); in high-vulnerability patients (OVS ≥2, n = 97), the benefit was markedly greater (HR = 0.363, P < 0.001). Causal forest analysis revealed substantial individual-level heterogeneity, identifying a subset of patients who may derive greater benefit from niraparib despite overall olaparib superiority.
Conclusion
This study shows baseline organ vulnerability significantly impacts PARP inhibitor efficacy. Olaparib outperforms niraparib in high-vulnerability patients, with comparable effects in low-vulnerability cases. While olaparib is generally superior, causal forest analysis reveals a subset benefiting more from niraparib, indicating treatment heterogeneity. Routine organ function assessment may guide personalized PARP inhibitor selection, especially where molecular testing is unavailable.